Bone Marrow CX3CL1/Fractalkine is a New Player of the Pro-Angiogenic Microenvironment in Multiple Myeloma Patients.

Valentina Marchica,Nicola Giuliani,Anna Corcione,Rosanna Vescovini,Cristina Mancini,Vito Pistoia,Elisa Ferretti,Emanuela Vicario,Domenico Ribatti,Fabrizio Accardi,Eugenia Martella,Benedetta Dalla Accardi,Denise Toscani,Angelo Vacca,Marina Bolzoni,Paola Storti

doi:10.3390/cancers11030321

Abstract

C-X3-C motif chemokine ligand 1 (CX3CL1)/fractalkine is a chemokine released after cleavage by two metalloproteases, ADAM metallopeptidase domain 10 (ADAM10) and ADAM metallopeptidase domain 17 (ADAM17), involved in inflammation and angiogenesis in the cancer microenvironment. The role of the CX3CL1/ C-X3-C motif chemokine receptor 1(CX3CR1) axis in the multiple myeloma (MM) microenvironment is still unknown. Firstly, we analyzed bone marrow (BM) plasma levels of CX3CL1 in 111 patients with plasma cell disorders including 70 with active MM, 25 with smoldering myeloma (SMM), and 16 with monoclonal gammopathy of undetermined significance (MGUS). We found that BM CX3CL1 levels were significantly increased in MM patients compared to SMM and MGUS and correlated with BM microvessel density. Secondly, we explored the source of CX3CL1 in MM and BM microenvironment cells. Primary CD138+ cells did not express CXC3L1 but up-regulated its production by endothelial cells (ECs) through the involvement of tumor necrosis factor alpha (TNFα). Lastly, we demonstrated the presence of CX3CR1 on BM CD14+CD16+ monocytes of MM patients and on ECs, but not on MM cells. The role of CX3CL1 in MM-induced angiogenesis was finally demonstrated in both in vivo chick embryo chorioallantoic membrane and in vitro angiogenesis assays. Our data indicate that CX3CL1, present at a high level in the BM of MM patients, is a new player of the MM microenvironment involved in MM-induced angiogenesis.

Highlights

Tumor-promoting inflammation and angiogenesis are hallmarks of cancer [1]
We firstly evaluated bone marrow (BM) CX3CL1 levels in our cohort of 111 patients, including 16 patients with monoclonal gammopathy of undetermined significance (MGUS), 25 with smoldering myeloma (SMM), and 70 with active MM, and 10 healthy donors (HD) as controls
CX3CL1 levels were significantly increased in the BM plasma of MM patients compared to HD, MGUS, and SMM patients (P < 0.0001, P < 0.0001, and P = 0.0011 respectively, Mann–Whitney test) (Figure 1A)

Summary

Introduction

Multiple myeloma (MM) is a hematological malignancy characterized by the tight dependence of malignant plasma cells (PCs) on the bone marrow (BM) microenvironment [2,3]. These relationships activate the production of several pro-inflammatory cytokines, chemokines and growth factors supporting MM cell survival, bone destruction, and an increased BM angiogenesis [4,5,6,7] that typically correlates with disease stage and prognosis [8,9,10]. C-X3-C motif chemokine ligand 1 (CX3CL1), known as fractalkine, is a protein of 373 amino acids with three main domains: Chemokine, mucin-like stalk, and transmembrane [11]. CX3CL1 can be found as a membrane-bound protein

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Discussion

Conclusion